Project Summary: Metastatic prostate cancer will claim the lives of over 30,000 men this year alone. There are no effective treatments that prevents disease progression. In prostate cancer, lipid production is known to drive tumor growth throughout the early and late stages. In addition to providing building blocks for tumor cell replication, lipids produced by tumors have been shown to repress immune activity, which allows tumors to grow unchecked. Clinically used immunotherapies which deactivate built-in anti- inflammatory pathways called immune checkpoints, have been highly effective at harnessing the tumor- killing abilities of immune cells. Unfortunately checkpoint blockade inhibitors are notoriously ineffective at treating metastatic prostate cancer. Studies have shown that tumors produce lipid metabolites, endogenous ligands of Liver-X-Receptor (LXR) that activate and suppress the function of immune cells. In line with this shutting down production of lipid metabolites in tumor cells reverses tumor suppression resulting in tumor destruction. As prostate cancer cells rely heavily on lipid synthesis, we postulated that prostate tumors produce LXR ligands to suppress immune function. Our studies have highlighted that prostate tumors produce lipids that activate LXR and suppress the activity of helper and effector T-cells as well as dendritic cells, all key cell types that direct a robust anti-tumor immune response. We theorized that prostate tumors specifically produce high activity LXR ligands and by suppressing LXR activity in immune cells we could stimulate tumor destruction. In this proposal, we will explore this hypothesis using three specific aims. We propose firstly to identify if prostate tumors produce unique lipids, LXR ligands, that are especially effective at suppressing immune cell activity. We also intend to determine if the concentrations of specific tumor lipids correlate with disease severity or responsiveness to treatment. Secondly, we will test if drugs which suppress LXR activation, can stimulate destruction of prostate tumors when used alone and probe whether these drugs can sensitize prostate tumors to checkpoint immunotherapies. Lastly, we will determine how LXR signaling regulates immune cell metabolism and the manner in which immune cells respond to prostate tumor growth. These studies should lead to the development of a novel dual activity immunotherapy for prostate cancer that has intrinsic cytotoxicity and immune stimulatory activity.